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We performed whole exome\u2010sequencing in a male patient from a consanguineous family, who presented with low\u2010 and intermediate molecular weight proteinuria, nephrocalcinosis and oligospermia. We identified a new potential player in tubular endocytosis, coiled\u2010coil domain containing 158 (CCDC158). The variant in <jats:italic>CCDC158<\/jats:italic> segregated with the phenotype and was also detected in a female sibling with a similar clinical kidney phenotype. We demonstrated the expression of this protein in kidney tubules and modeled its structure <jats:italic>in silico<\/jats:italic>. We hypothesized that the protein played a role in the tubular endocytosis by interacting with other endocytosis regulators, and used mass spectrometry to identify potential interactors. The role of CCDC158 in receptor\u2010mediated endocytosis was further confirmed by transferrin and GST\u2010RAP trafficking analyses in patient\u2010derived proximal tubular epithelial cells. Finally, as CCDC158 is known to be expressed in the testis, the presence of oligospermia in the male sibling further substantiated the pathogenic role of the detected missense variant in the observed phenotype. In this study, we provide data that demonstrate the potential role of CCDC158 in receptor\u2010mediated endocytosis, most likely by interaction with other endocytosis\u2010related proteins that strongly correlate with the proximal tubular dysfunction phenotype as observed in the patients. However, more studies are needed to fully unravel the molecular mechanism(s) in which CCDC158 is involved.<\/jats:p>","DOI":"10.1002\/jcp.31447","type":"journal-article","created":{"date-parts":[[2024,9,25]],"date-time":"2024-09-25T14:53:06Z","timestamp":1727275986000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["CCDC158: A novel regulator in renal proximal tubular endocytosis unveiled through exome sequencing and interactome analysis"],"prefix":"10.1002","volume":"239","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1952-6400","authenticated-orcid":false,"given":"Tjessa","family":"Bondue","sequence":"first","affiliation":[{"name":"Laboratory of Pediatric Nephrology, Department of Development and Regeneration KU Leuven Leuven Belgium"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Francesca","family":"Cervellini","sequence":"additional","affiliation":[{"name":"Telethon Institute of Genetics 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